RESUMO
Numerous processes of neuronal development and synaptic plasticity in the brain rely on the palmitoyl acyltransferase ZDHHC7, as it palmitoylates various synaptic and extrasynaptic proteins such as neural cell adhesion molecule (NCAM) or gamma-aminobutyric acid (GABAA) receptors. In addition, ZDHHC7 palmitoylates sex steroid hormone receptors and is, therefore, indirectly linked to mental disorders that often occur because of or in conjunction with stress. In this work, we investigated how ZDHHC7 affects stress responses in mice. For this purpose, genetically modified mice with a knockout of the Zdhhc7 gene (KO) and wild-type (WT) littermates of both sexes were exposed to acute stressors or control conditions and examined with regard to their behavior, brain microstructure, gene expression, and synaptic plasticity. While no behavioral effects of acute stress were found, we did find that acute stress caused reduced mRNA levels of Esr1 and Esr2 coding for estrogen receptor α and ß in the medial prefrontal cortex of male WT and KO mice. Strikingly, after acute stress only male KO mice showed reduced mean fiber lengths of the medioventral hippocampus. Furthermore, Zdhhc7-deficiency impaired synaptic plasticity in mice of both sexes, while acute stress improved it in females, but not in male mice. Taken together, our findings suggest that ZDHHC7 plays a modulatory role in the brain that leads to sex-specific stress responses, possibly due to estrogen receptor-mediated signaling pathways.
Assuntos
Caracteres Sexuais , Acetiltransferases , Aciltransferases , Animais , Feminino , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Knockout , Moléculas de Adesão de Célula Nervosa/metabolismo , Plasticidade Neuronal , Receptores de GABA-A , Estresse FisiológicoRESUMO
The palmitoyl acyltransferase ZDHHC7 belongs to the DHHC family responsible for the covalent attachment of palmitic acid (palmitoylation) to target proteins. Among synaptic proteins, its main targets are sex steroid receptors such as the estrogen receptors. When palmitoylated, these couple to membrane microdomains and elicit non-genomic rapid responses. Such coupling is found particularly in cortico-limbic brain areas which impact structure, function, and behavioral outcomes. Thus far, the functional role of ZDHHC7 has not been investigated in this context. To directly analyze an impact of ZDHHC7 on brain anatomy, microstructure, connectivity, function, and behavior, we generated a mutant mouse in which the Zdhhc7 gene is constitutively inactivated. Male and female Zdhhc7-/- mice were phenotypically compared with wild-type mice using behavioral tests, electrophysiology, protein analyses, and neuroimaging with diffusion tensor-based fiber tractography. Zdhhc7-deficiency impaired excitatory transmission, synaptic plasticity at hippocampal Schaffer collateral CA1 synapses, and hippocampal structural connectivity in both sexes in similar manners. Effects on both sexes but in different manners appeared in medial prefrontal cortical synaptic transmission and in hippocampal microstructures. Finally, Zdhhc7-deficiency affected anxiety-related behaviors exclusively in females. Our data demonstrated the importance of Zdhhc7 for assembling proper brain structure, function, and behavior on a system level in mice in a sex-related manner. Given the prominent role of sex-specificity also in humans and associated mental disorders, Zdhhc7-/- mice might provide a promising model for in-depth investigation of potentially underlying sex-specifically altered mechanisms.
Assuntos
Aciltransferases/deficiência , Comportamento Animal/fisiologia , Plasticidade Neuronal/genética , Fatores Sexuais , Transmissão Sináptica/genética , Animais , Ansiedade/genética , Potenciais Pós-Sinápticos Excitadores/genética , Hipocampo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos Knockout , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/metabolismo , Sinapses/genética , Sinapses/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
To find out if the astrocytic protein S100B involves its autocrine effects via RAGE we investigated the capacity of astrocytes to upregulate IL-6 and TNF-alpha expression by stimulation with S100B. The subcellular localization of RAGE expression at the cell surface membrane of cultured astrocytes was demonstrated by immunofluorescence microscopy, flow cytometry and Western blotting. S100B was able to stimulate IL-6 and TNF-alpha secretion in cultured astrocytes in a concentration- and time-dependent manner as shown by ELISA. S100B induced IL-6 and TNF-alpha secretion was blocked by the use of RAGE siRNA specific for knocking down RAGE expression.